Process for the optical resolution of (±)-cis or (±)-trans-permethric acid

0.42 g (2 mmols) of (±)-cis-permethric acid (hereinafter abbreviated as (±)-1) and 0.27 g (2 mmols) of (-)-1-(p-tolyl)ethylamine (hereinafter abbreviated as (-)-2) were added to 6 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight, after which the resultant crystals were filtered to obtain 0.31 g (0.90 mmols) of (+)-1/(-)-2 salt.

This salt was recrystallized from 3.9 ml of methanol to obtain 0.20 g (0.57 mmols) of (+)-1/(-)-2 salt. The yield based on the employed (±)-1 was 57.0%. m.p.=194°-199° C. and [α] 589 =28.3° (C=1, methanol). 1 ml of a 1N sodium hydroxide aqueous solution was added to the salt and subjected to ether extraction. To the resultant aqueous phase was added 1.1 ml of 1N hydrochloric acid, which was extracted with ether, followed by drying the resultant organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.12 g (0.57 mmols) of (+)-1. The yield was 57.0%. m.p.=88°-90° C. and [α] 589 =+31.6° (C=1, chloroform). The optical purity was 98.1%.

0.42 g (2 mmols) of (±)-1 and 0.44 g (2 mmols) of (+)-cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine (hereinafter abbreviated as (+)-3) were added to 11 m of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand for 4.5 hours and the resultant crystals were filtered to obtain 0.38 g (0.92 mmols) of (-)-1/(+)-3 salt.

The salt was recrystallized from 9 ml of methanol to obtain 0.31 g (0.73 mmols) of (-)-1/(+)-3 salt. The yield was 73.0% based on the employed (+)-1. m.p.=183°-185° C. and [α] 589 =+18.9° (C=0.6, methanol), 1.1 ml of a 1N sodium hydroxide solution was added to the salt, followed by ether extraction, 1.5 ml of 1N hydrochloric acid was added to the resultant aqueous phase and extracted with ether. The organic phase was dried with anhydrous sodium sulfate and subjected to distillation under reduced pressure to remove the solvent, thereby obtaining 0.13 g (0.62 mmols) of (-)-1. Yield=62.0%. m.p.=90°-91° C. and [α] 589 =-32.2° (C=1, chloroform), The optical purity was 100%.

4.18 g (20 mmols) of (±)-1 and 4.39 g (20 mmols) of (-)3 were added to 110 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand for 4.5 hours and the resultant crystals were filtered to obtain 3.78 g (8.81 mmols) of (+)-1/(+)-3 salt. The yield based on the starting (±)-1 was 88.1%. m.p.=183°-185° C. and [α] 589 =18.4° (C=0.7, methanol). 4.4 ml of a 3N sodium hydroxide solution was added to the salt and subjected to ether extraction. 3.2 ml of 6N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 1.83 g (8.75 mmols) of (+)-1. Yield=87.5%. m.p.=87.90° C. and [α] 589 =+30.1° (C=1.4, chloroform). The optical purity was 93.5%.

4.18 g (20 mmols) of (±)=1 and 3.50 g (16 mmols) of (+)-3 were added to 90 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand for 4.5 hours and the resultant crystals were filtered to obtain 3.64 g (8.50 mmols) of (+)-1/(-)-3 salt. The yield based on the starting (±)-1 was 85.0%. m.p.=180°-181° C. and [α] 589 =++17.0° (C=0.7, methanol). 4.0 ml of a 3N sodium hydroxide solution was added to the salt and subjected to ether extraction. 2.5 ml of 6N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 1.77 g (8.46 mmols) of (-)-1. Yield=84.6%. m.p.=85°-88° C. and [α] 589 =-29.3° (C=1.0, chloroform). The optical purity was 93.5%.

Reference 1

4.18 g (20 mmols) of (±)-1 and 4.23 g (20 mmols) of (-)-1-phenyl-2-(p-tolyl)ethylamine (hereinafter abbreviated as (-)-4) were added to 30 ml of methanol and heated for dissolution, followed by cooling to room temperature. The solution was allowed to stand for 4.5 hours and the resultant crystals were filtered to obtain 5.17 g (12.3 mmols) of crude (-)-1/(+)-4 salt.

The salt was recrystallized from 19 ml of methanol to obtain 3.15 g (7.5 mmols) of (-)-1/(+)-4 salt. The yield based on the starting (±)-1 was 75%. [α] 589 =-27.8°. 3 ml of a 3N sodium hydroxide solution was added to the salt and subjected to ether extraction. 1.5 ml of 6N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, after which the organic phase was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain 1.52 g of (-)-1. Yield=73%. [α] 589 =-15.4° (C=1.0, cloroform). The optical purity was found to be 47.7%.

0.42 g (2 mmols of (±)-trans-permethric acid (hereinafter abbreviated as (±)-11) and 0.33 g (2 mmols) of (+)-1-(p-isopropylphenyl)ethylamine (hereinafter abbreviated as (+)-12) were added to 3 ml of methanol and heated for dissolution, followed by cooling down to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 0.23 g (0.62 mmols) of (+)-11/(+)-12 salt. The yield based on the starting (+)-11 was 62.0%. m.p.=186°-192° C. and [α] 589 =+13.5° (C=1.5, methanol). 0.7 ml of a 1N sodium hydroxide solution was added to the salt and subjected to ether extraction. 0.8 ml of 1N hydrochloric acid was added to the resultant aqueous phase and subjected to extraction with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.13 g (0.62 mmols) of (+)-11, Yield=62.0%, m.p.=69°-76° C. and [α] 589 =+26.3° (C=1.2, chloroform). The optical purity was 73.7%.

0.42 g (2 mmols) of (±)-11 and 0.27 g (2 mmols) of (-)-1-ethylbenzylamine (hereinafter abbreviated as (-)-13) were added to 5 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 0.21 g (0.61 mmols) of (+)-11/(+)-13 salt. The yield based on the starting (+)-11 was 61.0%. m.p.=186°-191° C. and [α] 589 =+16.6° (C=1.1, methanol). 0.7 ml of a 1N sodium hydroxide solution was added to the salt and subjected to ether extraction. 0.8 ml of 1N hydrochloric acid was added to the resultant aqueous phase and subjected to extraction with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.12 g (0.57 mmols) of (+)-11. Yield=57.0%, m.p.=69°-76° C. and [α] 589 =+27.6° (C=1.2, chloroform). The optical purity was 77.3%.

160 g (7.65 mmols) of (±)-11 and 1.03 g (7.62 mmols) of (-)-13 were added to 16 ml of methanol, and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 0.86 g (2.5 mmols) of (+)-11/(-)-13 salt. This salt was recrystallized from 5 ml of methanol to obtain 0.70 g (2.03 mmols) of (+)-11/(-)-13 salt. The yield based on the starting (+)11 was 53.1%. m.p.=187°-193° C. and [α] 589 =+18.9° (C=1), methanol). 3 ml of a 1N sodium hydroxide aqueous solution was added to the salt and extracted with ether. 4 ml of 1N hydrochloric acid was added to the resultant aqueous phase and subjected to extraction with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.41 g (1.96 mmols) of (+)-11. Yield=51.2%, m.p.=67°-70° C., and [α] 589 =+34.1° (C=1.8, chloroform). The optical purity was 95.5%.

2.09 g (10 mmols) of (+)-11 and 2.19 g (10 mmols) of (-)-3 were added to 10 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 1.81 g (4.23 mmols) of (+)-11/(-)-3 salt. The salt was recrystallized from 6.5 ml of methanol to obtain 1.20 g (2.80 mmols) of (+)-11/-(-)-3 salt. The yield on the starting (+)-11 was 56.0%. m.p.=160°-162° C. and [α] 589 =+9.94° (C=1.2, methanol). 3.1 ml of a 1N sodium hydroxide solution was added to the salt and subjected to ether extraction. 3.5 ml of 1N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.58 g (2.77 mmols) of (+)-11. Yield=55.4%, m.p.=67°-72° C., and [α] 589 =+34.7° (C=1, chloroform). The optical purity was 97.2%.

2.09 g (10 mmols) of (±)-11 and 1.75 g (8 mmols) of (-)-3 were added to 8 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 1.67 g (3.90 mmols) of (+)-11/(-)-3 salt. The salt was recrystallized from 5.5 ml of methanol to obtain 1.15 g (2.68 mmols) of (+)-11/-(-)-3 salt. The yield on the starting (+)-11 was 53.6%. m.p.=155°-160° C. and [α] 589 =+9.19° (C=1.3, methanol). 3.3 ml of a 1N sodium hydroxide solution was added to the salt and subjected to ether extraction. 4 ml of 1N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.53 g (2.53 mmols) of (+)-11. Yield=50.6%, m.p.=68°-71° C., and [α] 589 =+34.8° (C=1.3, chloroform). The optical purity was 97.5°.

Reference 2

2.09 g (10 mmols) of (±)-11 and 1.35 g (10 mmols) of (+)-2 were added to 10 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 2.05 g of a salt of both compounds. [α] 589 =+4.1° (C=1, methanol). This salt was recrystallized from 7.6 ml of methanol to obtain 1.09 g of the salt. [α] 589 =+4.4° (C=1, methanol). 5 ml of a 1N sodium hydroxide solution was added to the salt and subjected to ether extraction. 1.1 ml of 1N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.65 g of (±)-11. [α] 589 =-0.39° (C=1, chloroform) and optical purity=1.1%.

Reference 3

2.09 g (10 mmols) of (±)-11 and 1.21 g (10 mmols) of (-)-1-phenylethylamine were added to 7.6 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 1.52 g of a salt of both compounds. [α] 589 =-5.23° (C=1, methanol). 5 ml of a 1N sodium hydroxide solution was added to the salt and subjected to ether extraction. 1.1 ml of 1N hydrochloric acid was added to the resultant aqueous phase and extracted with ether, followed by drying the organic phase with anhydrous sodium sulfate and removing the solvent by distillation under reduced pressure to obtain 0.96 g of (-)-11. [α] 589 =-5.21° (C=1, chloroform) and optical purity=14.6%.

Reference 4

2.09 g (10 mmols) of (±)-11 and 1.77 g (10 mmols) of (-)-3-methyl-2-(p-tolyl-butylamine were added to 22 ml of methanol and heated for dissolution, followed by gradual cooling to room temperature. The solution was allowed to stand overnight and the resultant crystals were filtered to obtain 2.51 g of a salt of both compound. [α] 589 =-9.82° (C=1, methanol). The salt was recrystallized from 22.6 ml of methanol to obtain 0.89 g of the salt. [α] 589 =-8.60° (C=1, methanol).

5 ml of a 1N sodium hydroxide solution was added to the salt. 1.1 ml of 1N hydrochloric acid was added to the resultant aqueous phase and subjected to ether extraction, after which the organic phase was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain 0.48 g of (±)-11. [α] 589 =-0.43° (C=1, chloroform) and optical purity=1.1%.

Reference 5

0.55 g (2.63 mmols) of (±)-11 and 0.45 g (2.63 mmols) of (+)-1-(1-naphthyl)ethylamine were added to 5.3 ml of methanol and heated for dissolution, followed by cooling to room temperature and allowing to stand overnight. The resultant crystals were removed by filtration to obtain 0.42 g of a salt of both compounds. The yield based on the total amount of the (±)-trans-permethric acid was 42%.

This salt was decomposed with sodium hydroxide and hydrochloric acid to obtain 0.23 g (1.1 mmols) of (+)-transpermethric acid. [α] 589 =+0.42° (C=1.7, chloroform) and optical purity=1.2%.